Psychological interventions for early-phase schizophrenia: protocol for a systematic review and network meta-analysis

Introduction Treating the early phase of schizophrenia is crucial for preventing further episodes and improving quality of life, functioning, and social inclusion. Pharmacotherapies are first-line treatments, but have limitations. There is consensus on the need for non-pharmacological interventions for individuals in the early phase of schizophrenia. Several psychological interventions have shown promising effects; however, their comparative effectiveness remains largely unknown. To address this issue, a network meta-analysis will be performed. We aim to develop a hierarchy of existing psychological treatments concerning their efficacy and tolerability, which will inform treatment guidelines. Protocol Randomized controlled trials (RCTs) investigating psychological interventions for first-episode psychosis, first-episode schizophrenia, or early phase schizophrenia will be included. The primary outcome will be overall schizophrenia symptoms (measured up to 6 and 12 months, and at the longest follow-up) and relapse as a co-primary outcome. Secondary outcomes are premature discontinuation; change in positive, negative, and depressive symptoms of schizophrenia; response; quality of life; overall functioning; satisfaction with care; adherence; adverse events; and mortality. The study selection and data extraction are performed by two independent reviewers. We will assess the risk of bias of each study using the Cochrane Risk of Bias tool 2 and evaluate the confidence in the results using Confidence in Network Meta-Analysis (CINeMA). Subgroup and sensitivity analyses will be conducted to explore heterogeneity and assess the robustness of our findings. Discussion This systematic review and network meta-analysis aims to compare multiple existing psychological interventions, establishing which are best for symptom reduction, relapse prevention, and other important outcomes in early phase schizophrenia. Our results may provide practical guidance concerning the most effective psychological intervention to reduce symptom severity and the societal burden associated with the disorder.


Introduction
Treating the early phase of schizophrenia is crucial for preventing further episodes and improving quality of life, functioning, and social inclusion.Pharmacotherapies are first-line treatments, but have limitations.There is consensus on the need for non-pharmacological interventions for individuals in the early phase of schizophrenia.Several psychological interventions have shown promising effects; however, their comparative effectiveness remains largely unknown.To address this issue, a network meta-analysis will be performed.We aim to develop a hierarchy of existing psychological treatments concerning their efficacy and tolerability, which will inform treatment guidelines.Any reports and responses or comments on the Randomized controlled trials (RCTs) investigating psychological interventions for first-episode psychosis, first-episode schizophrenia, or early phase schizophrenia will be included.The primary outcome will be overall schizophrenia symptoms (measured up to 6 and 12 months, and at the longest follow-up) and relapse as a co-primary outcome.Secondary outcomes are premature discontinuation; change in positive, negative, and depressive symptoms of schizophrenia; response; quality of life; overall functioning; satisfaction with care; adherence; adverse events; and mortality.The study selection and data extraction are performed by two independent reviewers.We will assess the risk of bias of each study using the Cochrane Risk of Bias tool 2 and evaluate the confidence in the results using Confidence in Network Meta-Analysis (CINeMA).Subgroup and sensitivity analyses will be conducted to explore heterogeneity and assess the robustness of our findings.

Discussion
This systematic review and network meta-analysis aims to compare multiple existing psychological interventions, establishing which are best for symptom reduction, relapse prevention, and other important outcomes in early phase schizophrenia.Our results may provide practical guidance concerning the most effective psychological intervention to reduce symptom severity and the societal burden associated with the disorder.

Introduction
Schizophrenia is a severe and often life-long disorder that ranks among the 20 top causes of disability. 1 The typical age of onset is in the early 20s, 2 often resulting in a dramatic reduction in patients' quality of life, social functioning, educational attainment, and socioeconomic status.There is an agreement on the importance of treating this critical phase to prevent further episodes. 3,4Different definitions have been used to refer to the early course of the illness, and the term 'first episode' is often used in a broader sense. 5Research focuses on the early phases, including the second or third episode, usually with a time from onset criterion. 5Schizophrenia can also manifest in the prelude to the full onset of symptoms through early warning signs such as social withdrawal, mistrust, sleep disturbances, and many more. 6However, these are not definitive indicators of the disorder but can be viewed as early warning signs.
Pharmacological interventions are a first-line treatment for schizophrenia but have several limitations, including limited response, high incidence of disabling side effects, and poor adherence to treatment. 7,8Antipsychotics can also be problematic for patients with medical comorbidities, tolerability problems, or pregnancy.Overall, 24% of patients with a first episode of psychosis did not respond when treated with antipsychotics, 9 and 26% experienced relapse. 10Furthermore, few antipsychotics are licensed for people under 18 years of age and tolerability problems are higher in this subpopulation. 4The resulting burden on patients, relatives, and society as a whole is substantial, with acute symptoms and relapses often leading to costly hospitalizations, job loss, and strained relationships.As a result, there is a strong agreement on the need for non-pharmacological interventions in patients in the early phase of schizophrenia. 4 Knowledge of the psychological interventions that are most efficacious in improving symptoms and preventing relapse in this critical population may improve treatment planning and resource allocation in the healthcare sector.
Previously, evidence regarding psychological interventions for early phase schizophrenia has been synthesized in pairwise meta-analyses that examined single psychological interventions, such as CBT and family therapies.The effects were mainly compared to those of usual care (TAU), with promising results on social functioning, 11,12 relapse, [12][13][14] REVISED Amendments from Version 1 To address the reviewer remarks, we provided additional details concerning the definition of early phase schizophrenia and the aims of our network meta-analysis.
Any further responses from the reviewers can be found at the end of the article and psychotic symptoms. 14Our group conducted a Cochrane review investigating the role of CBT for this population compared to TAU. 15 Early intervention teams, providing collaborative care including medication, psychotherapy, psychoeducation, and occupational, educational, and employment support, have also shown an effect in reducing dropouts and improving functioning compared to TAU. 16 Three network meta-analyses have been conducted on psychological interventions for patients with schizophrenia: one on positive symptoms excluded patients with a first episode 17 ; one was strictly focused on relapse prevention, including only studies where relapse was the primary outcome, and found only a small number of studies on patients in the early phase 18 ; the third only considered overall symptoms as outcome, with searches dating back to 2016. 19Therefore, no up-to-date evidence can be derived from these NMAs in patients in the early phase of schizophrenia.However, a very recent network meta-analysis examined psychological interventions for the treatment of early psychosis and demonstrated positive effects. 20Nevertheless, this analysis was based on a limited number of studies, investigated only a small number of outcomes, and had no special focus on schizophrenia. 20 summary, the current evidence on psychological treatments for early stage schizophrenia is limited to pairwise metaanalyses that investigate single interventions (such as cognitive behavioral therapy and family interventions), as well as to NMAs that either do not focus on the corresponding population or include a very small number of studies or outcomes.Thus, the most efficacious and acceptable psychological treatments for patients with schizophrenia in the early phase of the disorder are currently unclear.This underlines the need for a network meta-analysis to produce a comprehensive synthesis of all randomized evidence, focusing on this particular population.

Objective
The goal of this systematic review and network meta-analysis is to synthesize the relative efficacy of all available psychological treatments in one analysis.We aim to combine both direct and indirect evidence to create effect estimates, even for treatments that have never been directly compared in a trial.Furthermore, we plan to extend the existing knowledge on the topic by examining multiple endpoints, including symptom severity, quality of life, functioning, and relapse rates.Finding out which psychological intervention is most efficacious in treating patients with schizophrenia in the early phase can have a decisive impact on preventing chronicity of the illness.The results of this work may hold significant relevance for resource planning in treatment.

Protocol
This systematic review and network meta-analysis protocol followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-P) statement extension for network meta-analysis. 21Appendix 1 provides the PRISMA-P checklist.This protocol was registered in PROSPERO (CRD42024514287).

Characteristics of studies
We will include (i) randomized controlled trials comparing (ii) a psychological intervention to (iii) a control group (waitlist, treatment as usual, psychological placebo, or other psychosocial or psychological treatments).Psychological placebo will be defined as any condition aimed at controlling the time spent with a therapist, without delivering any bona fide psychotherapeutic content (e.g., recreational therapy, activity groups).We expect that, in the majority of studies, psychological intervention will be provided in addition to standard care, which usually includes antipsychotic medication.If we find studies in which psychological intervention is administered without concomitant pharmacotherapy, we will consider these studies as well.

Characteristics of participants
We will consider trials in patients with a recent first-time diagnosis of psychosis, first-episode schizophrenia, or early phase schizophrenia, as per the inclusion criteria of specific studies.In cases of "early-phase schizophrenia" or "recentonset psychosis", we will accept a maximum duration of illness of 5 years.We will also include studies conducted in specialized early intervention centers since they target the population in question.We will include studies with participants aged 16 years or older, allowing us to capture the variability in the age of onset of schizophrenia.Studies focusing on participants over the age of 65 years as part of their inclusion criteria or those investigating late-onset psychosis will be excluded.Participants must exhibit symptoms that match the criteria for schizophrenia or related disorders (schizophreniform, schizoaffective or delusional disorder, however diagnosed).We will exclude studies that only include patients with bipolar mania, bipolar depression, substance-induced disorders, and psychoses of organic origin.We enforce this criterion because, despite unavoidable overlap, our focus is on schizophrenia and schizophreniarelated disorders (schizoaffective disorder and delusional disorder).We will exclude studies in "at risk of psychosis" or "prodrome" populations because such patients do not experience full-blown psychotic symptoms by definition.If a study included participants with other diagnoses, we include it if participants with psychosis (as defined above) comprised at least 50% of the participants.There will be no restrictions on sex, ethnicity, or setting.

Interventions
We will consider all psychological interventions that meet the classification criteria proposed by the Cochrane Common Mental Disorder Group (former CCDAN). 22These classification criteria have already been employed in a previous meta-analysis on schizophrenia, in which early phase participants were not included. 17We do not expect that studies and data will be available for all interventions mentioned in the classification, but if they do, they will be considered.Thus, we will consider psychotherapies (e.g., cognitive behavioral therapy, "third-wave" cognitive behavioral therapies, such as acceptance and commitment therapy, mindfulness and metacognitive training, psychodynamic therapy, art therapy, and music therapy), treatments that are often routinely provided in clinical settings, such as supportive therapy and psychoeducation, interventions focused on functioning (e.g., social skills training), and family interventions.Newly developed treatments that are not included in the list will also be considered for inclusion (e.g., virtual reality and AVATAR therapy).Organization of care-oriented interventions (e.g., case management, assertive community treatment) and supported employment will not be considered, because they have other aims, and it will not be meaningful to analyze their efficacy in contrast to the ones mentioned above.

Primary outcome
Our primary outcome was the severity of schizophrenia symptoms, measured by rating scales such as the Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), or any other validated scale for the assessment of overall symptoms of schizophrenia.Based on our experience, we expect these scales to be used in almost all the trials.If only results of other rating scales are reported, they will only be used if the instrument has been validated in psychosis and published in a peer-reviewed journal, because non-validated schizophrenia scales tend to exaggerate differences. 23lapse will be the primary outcome.For patients in the early phase, it is crucial to prevent relapse because the risk of chronicity increases with every episode.If more measures of relapse are reported, we will prioritize measures according to the following order: (i) operationalized criteria, (ii) hospital admissions due to psychopathology, and (iii) clinical judgement.

Secondary outcomes
We will also consider a broad collection of outcomes that may be informative for patients, clinicians, and guideline makers if available in the primary studies.We will focus on validated and established scales.Other rating scales will only be used if the instrument has been published in a peer-reviewed journal, because non-validated schizophrenia scales tend to exaggerate differences. 24Premature discontinuation ("dropout") due to any reason: All-cause discontinuation ('dropping out') due to any reason combines efficacy, tolerability, and other factors and can therefore been considered as a measure of 'acceptability of treatment'.25 We will also separately report the number of dropouts due to inefficacy of the treatment and worsening of clinical conditions.
2. Change in positive, negative and depressive symptoms of schizophrenia: According to the respective subscales of the PANSS or the "Scales for Assessment of Positive/Negative Symptoms" (SAPS, SANS), the Calgary Depression Scale for Schizophrenia, the Hamilton Depression Rating Scale, the Montgomery-Åsberg Depression Scale, or other validated symptom scales.These are important components of the psychopathology of schizophrenia and contribute considerably to the burden associated with the disease.

Response:
The number of responders is defined based on validated rating scales.We will extract the percentage of participants who experienced at least a 20% reduction in PANSS or BPRS scores or a minimum improvement on the Clinical Global Impression (CGI) scale.These findings can be considered equivalent and meaningful for patients in the early phases of the disorder. 26 Quality of Life: The importance of this outcome was highlighted by our patient representatives collaborators and recommended by institutions such as the German "Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen" (IQWIG).We will accept any published, validated rating scale (e.g."Heinrichs quality of life scale"; Quality of Life Scale, QOLS).
5. Overall Functioning: Measured by rating scales such as the Global Assessment of Functioning (GAF), Psychosocial Performance Scale (PPS), or any other published rating scale.We will also record the number of participants employed, having a relationship, and living independently as more direct measures of functioning, although we anticipate that this will rarely be reported.
6. Satisfaction with care: We will measure participants' satisfaction with care using any validated scale.This outcome was also highlighted as relevant by our patient representatives.
7. Adherence: The extent to which psychological treatment can contribute to patients' compliance with treatment in general will also be considered.We will accept any published rating scale (e.g., "Adherence Therapy Patients Satisfaction Questionnaire," "Adherence Rating Scale").
8. Adverse events: We will collect any available information in the included studies about this outcome, using the classification proposed by Linden et al. 27 : (i) emergence of new symptoms, (ii) deterioration of existing symptoms, (iii) lack of improvement or deterioration of illness, (iv) prolongation of treatment, (v) strains in the patient-therapist relationship, (vi) therapy dependency, (vii) strains or changes in family relations, (viii) strains or changes in work relations, (ix) any change in the life circumstances of the patient, and (x) stigmatization.We also included cases of abuse.Patient noncompliance is already covered as a separate outcome and is not considered here.Suicide attempts and other possible adverse events related to psychological treatment should also be considered.
9. Death: Psychological treatment may reduce overall mortality, particularly suicidality.We examine this outcome separately in terms of (i) death for any reason, (ii) death due to natural causes, and (iii) death due to suicide.

Search strategy
We searched the most important electronic databases for relevant publications: BIOSIS, CINAHL, Cochrane CEN-TRAL, Dissertation Abstracts, EMBASE, LILACS, MEDLINE, PsycINFO, and Pubmed), including clinical trial websites such as Clinicaltrials.govand the International Clinical Trials Registry Platform of the World Health Organization (http://apps.who.int/trialsearch).Additionally, we will search previous reviews, statements of guidelines, and specific relevant journals concerning psychological treatments for schizophrenia to retrieve other studies.We will contact the first authors of the included studies in case of missing information.The search strings are provided in the Supplementary Material (Appendix 2). 52entification and selection of studies Two reviewers from our team will independently screen the search results for general inclusion criteria using the online tool Rayyan. 28Disagreements will be resolved by discussion, and, where doubts remain, we will acquire the full article for further inspection.Once the full articles were obtained, the two reviewers will independently decide whether the studies meet the review criteria.If disagreement cannot be clarified by discussion, we will consult a senior researcher (SL, IB) or seek further information from the authors.

Data extraction
Two reviewers will independently extract data from all selected trials using specifically developed forms in a Microsoft Access database.The forms will be piloted on a random sample of ten randomized controlled trials (RCTs).Disagreements will be resolved by discussion with a third senior researcher (SL, IB).The authors will be contacted if needed to resolve disagreements.The following data will be extracted from each included study: (i) general study information, (ii) information on methodology, (iii) characteristics of study participants, (iv) characteristics of psychological interventions, and (v) outcome measures.

Measurement of treatment effect
For continuous outcomes, we will calculate the standardized mean difference (SMD) as the effect measure, since we expect studies to use different rating scales for the measurement of overall schizophrenia symptom severity.We will prefer results obtained with imputation methods to handle missing data over complete data; results from mixed models of repeated measurement (MMRM) or multiple imputations will be preferred over last observation carried forward (LOCF).
In case of missing summary statistics data, we will contact the authors of the primary study.When standard errors (SEs) are presented instead of standard deviations (SDs), the former are converted to standard deviations.If both are missing, we estimate SDs from confidence intervals, t-values, or p-values, as described in the Cochrane Handbook for Systematic Reviews. 29If none of these options is viable, we will contact the study authors.When no information could be obtained, we derive SDs from those of the other studies using a validated imputation technique. 30ds ratios will be used to calculate dichotomous outcomes.Everyone allocated to the intervention will be counted to determine whether they have completed the follow-up.For beneficial outcomes, patients (e.g., responses) with missing outcome data will be assumed to be non-cases.All effect sizes are presented with 95% confidence intervals (CIs).
The primary time point of interest is 12 months, which, according to Cochrane, can be considered a medium term.The primary outcomes will also be collected and analyzed for up to six months (short-term) and more than 12 months (long-term).

Risk of bias assessment
Two reviewers will independently assess the risk of bias of the primary outcomes using the Cochrane Risk of Bias tool, version 2 (RoB 2.0). 31Disagreements between the two reviewers will be discussed with a third senior reviewer (SL, IB).We will not include studies whose sequence generation was judged to show a high risk of bias in the data analyses.
The impact of the risk of bias will be analyzed using a sensitivity analysis.

Data analysis Conventional pairwise meta-analyses
First, we will perform conventional pairwise meta-analyses for specific comparisons covered by the included trials.If the requirements for a network meta-analysis are not met, we present only the findings from pairwise syntheses.Pairwise meta-analyses will be based on a random-effects model with τ 2 quantified using the restricted maximum likelihood estimator. 32The confidence intervals of the pooled effect will be adjusted using the method described by Hartung and Knapp. 33,34sessment of heterogeneity Heterogeneity will be quantified using the estimated between-study heterogeneity variance (τ 2 ) and will be presented using 95% prediction intervals.In the network meta-analysis model, heterogeneity variance is assumed to be common across the various treatment comparisons, and the empirical distributions are used to characterize the amount of heterogeneity as low, moderate, or high using the first and third quantiles. 35,36Potential reasons for heterogeneity will be explored using subgroup analysis and meta-regression.

Network meta-analysis
Network meta-analysis allows the combination of direct and indirect evidence for all relative treatment effects, and can therefore provide effect estimates with maximum power and increased precision. 37The NMA models will be implemented using the frequentist graph-theoretical framework developed by Rücker. 38NMA models are based on the transitivity assumption, which is checked by investigating whether potential clinical and methodological effect modifiers (see subgroup analysis) are similarly distributed across studies.We will use the design-by-treatment interaction test that evaluates inconsistency from all possible sources in the network jointly, 39 as well as the SIDE test (separating indirect evidence from direct evidence), 40 assessing the agreement of indirect and direct evidence for every possible comparison in the network.In the case of evidence of inconsistency or intransitivity, we investigated possible sources.Small or moderate amounts of inconsistency will be further explored by network meta-regression and subgroup analyses, using the potential effect modifiers listed below.We estimated the probability for each intervention to be ranked at each possible place, given the relative effect sizes estimated in the NMA.We obtain a hierarchy of competing interventions using a frequentist extension of the surface under the cumulative ranking curve (P-score), as well as the mean ranks. 41

Subgroup analysis and meta-regression
We plan to conduct the following subgroup analyses and network meta-regressions of the primary outcomes to investigate the impact of potential effect modifiers: a) age, b) patients clearly experiencing a first episode versus broader criteria (e.g., time criteria or second episode), c) duration of illness, d) number of sessions, e) manualized vs. nonmanualized interventions, f) dose of antipsychotic treatment, and g) baseline severity of symptoms.

Sensitivity analyses
We plan to conduct the following sensitivity analyses of the primary outcomes by excluding: a) studies that did not use a blind outcome assessor (open studies); b) studies presenting only completer analyses; c) overall high risk of bias studies; d) studies with researchers' allegiance; and e) studies that did not use operationalized diagnostic criteria.

Small study effects and publication bias
We will explore the association between study size and effect size using a comparison-adjusted funnel plot method. 42 comparison of more than 10 studies will be plotted in a contour-enhanced funnel plot.Any asymmetry observed can be attributed to systematic differences between small and large studies (e.g., differences in the risk of bias or recruitment), true heterogeneity, or publication bias.If significant small trial effects are identified, we will account for them via network meta-regression using a measure of study uncertainty (e.g., variance) as a covariate. 42,43The possibility of reporting bias across the entire network will be assessed using the RoB-MEN framework. 44,45aluating the confidence in estimates The confidence in estimates of the main outcomes will be evaluated with the framework Confidence in Network Meta-Analysis (CINeMA), 46 an adaptation of the Grading of Recommendations Assessment, Development, and Evaluation framework (GRADE) specifically developed for NMA.The possibility of reporting bias across the entire network will be assessed using the RoB-MEN framework. 44The margin of equivalence for continuous endpoints will be an SMD of 0.2 47 and an OR of 0.8 (1.25) for dichotomous outcomes (cf.Ref. 48).

Statistical software
Analyses will be conducted in R. A pairwise meta-analysis will be performed using the "meta" package. 49The frequentist NMA model will be fitted using the "netmeta" package. 50Network meta-regression will be performed in a Bayesian framework using models implemented in JAGS, 51 assuming a weakly informative prior for the between-study heterogeneity variance τ 2 .

Discussion
This network meta-analysis will examine the effectiveness of psychological interventions in the treatment early-phase schizophrenia.We will maximize statistical power by combining direct and indirect comparisons and measuring the relative effects and adverse events of different psychological interventions with regard to various outcome measures such as symptomatology, relapses, and quality of life.Based on these findings, it is possible to identify the most effective therapy.Thus, the results have great potential to improve the guidelines and treatment of people with schizophrenia.
Network meta-analysis currently presents the most advanced way to summarize evidence from multiple (in theory, interchangeable) treatments, and the results obtained are highly dependent on the quality of the included studies.We expect different definitions for the first episode and early phase schizophrenia.Considering the variability, we selected broad inclusion criteria regarding the definition to identify a wide range of eligible studies and carefully scrutinize the specific definitions from each study.To investigate the potential resulting heterogeneity, corresponding meta-regression and subgroup analyses will be conducted.
By improving patients' symptoms and well-being, evidence-based information on efficacious psychological treatments may also reduce the need for medications and the burden of side effects.This evidence-based information is important for the choice of individual treatment plans from a shared decision-making perspective.Our results will show how well various psychological treatments have been studied so far and the limitations of the current evidence base, allowing meaningful planning of future trials.Overall, this should result in a major step forward in terms of individualized treatment of schizophrenia, which can lead to changes in the German and international guidelines.
Extended data research: Which psychological interventions have already been tested for their potential benefit in the treatment of so-called early-phase schizophrenia?Among all the interventions that have been evaluated so far, which one is currently considered the best option for enhancing therapy offerings in the early stages of the illness?
To scientifically and thoroughly answer these two closely related questions, the authors first plan to compile all randomized controlled trials conducted on such interventions so far through a systematic review.In the second step, they consequently intend to use modern statistical techniques, specifically a network meta-analysis (NMA), to comprehensively compare the effectiveness and tolerability of the various psychotherapies and other psychological or psychosocial treatments used in these clinical studies.
Their first paper in this context follows the meanwhile well-established practice in therapeutic research of prepublishing the study protocol.This approach provides an opportunity to get acquainted with the intended research project and also allows for suggestions for any necessary improvements before the study begins.This makes a lot of sense, especially for an ambitious and complex project like the planned comparison of all available options in an important therapeutic application field.Because when it comes to evidence syntheses, especially for the development of clinical guidelines, it is crucial to ensure that the proposed strategies for study selection and evaluation analysis truly offer realistic chances of generating new evidence-basing.
Looking back at conventional meta-analyses, which only ever compared two treatment options with each other, NMAs certainly represent a significant methodological advanced development that is now clearly preferred by all relevant institutions in international treatment research.However, NMAs have also proven to be more prone to misinterpretation than pairwise comparisons, especially when the included studies are too dissimilar, too heterogeneous in their outcomes, or when the directly measured and indirectly derived evidence is too inconsistent.This is precisely why the pre-publication of the study protocol is particularly important for planned "mixed treatment" or "multiple treatment meta-analyses," as NMAs are also known.Only full transparency and critical reflection of the study design within the relevant scientific community can at least to a great extent reliably ensure that in retrospect the application criteria for NMAs had not been met.
However, the planned NMA would not be the first to focus on psychological interventions for patients with schizophrenia.The authors are well aware that there have already been three such intervention comparisons using the new network method.However, they argue that the studies included in these previous NMAs either focused only on certain aspects of symptomatology [1]  and disease progression [2] or were conducted in the distant past [3].In contrast, their systematic review and new NMA, which they announce with the pre-publication of this study protocol, are designed to be much more comprehensive and up-to-date in terms of the planned study selection.
Indeed, the protocol communications regarding the eligibility criteria and the primary and secondary outcomes establish an extraordinarily broad scope for data collection.All psychological interventions that meet the classification criteria proposed by the Cochrane Common Mental Disorders Group (formerly CCDAN) are to be considered if they have been investigated in randomized controlled trials.The authors expect that various forms of therapy, including art and music therapy, social skills training, and family interventions, were administered in the majority of studies in addition to standard care, which usually included antipsychotic medication.This further strongly emphasizes that their analysis genuinely aims to improve the evidence base for current clinical practices.
All specifications about the methods, including those related to the search strategy, the identification of selection of studies, and data extraction, as well as those concerning the most important aspect of the planned investigation, namely data analysis, appear plausible.If all these steps can be implemented as planned, it should indeed be possible to establish a ranking from the best to the worst psychological interventions.However, a potential issue is also emerging here that cannot yet be determined before the systematic review has been carried out as to whether it could significantly jeopardize the applicability of the planned NMA.
The studies approved under the protocol are supposed to focus on participants aged over 16 and under 65 years with a recent first-time diagnosis of psychosis, first episode schizophrenia, or earlyphase schizophrenia.The authors intend to define the somewhat unclear terms "early-phase schizophrenia" or "recent onset psychosis" by a maximum illness duration of 5 years.All participants in the approved studies must present or have presented full-blown psychotic symptoms.For this reason, studies on populations at risk of psychosis or in the prodrome phase are excluded, even though the psychological interventions of interest here actually play an even greater role as recognized first-choice prevention strategies in those populations [4].Ultimately, all studies relating to manifest schizophrenic, schizoaffective, and delusional disorders with a duration of up to 5 years are included, regardless of how many psychotic episodes have occurred within that period.However, this is a very broad inclusion range, for which the title "early-phase schizophrenia" might seem misleading.The authors themselves are concerned about a potential resulting heterogeneity that could jeopardize the requirements for comparability of all included studies that apply to the NMAs.Therefore, it would be helpful if they could elaborate further on their suggested methods for capturing and managing such heterogeneity and how they intend to deal with it.
However, from my perspective, this is the only minor improvement suggestion for a study protocol that otherwise indeed promises to be a major step forward in terms of individualized treatment for schizophrenia

Stefano Barlati
University of Brescia, Brescia, Italy 1) SUMMARY OF ANALYZED ARTICLE The present study protocol for a systematic review and network meta-analysis regarding psychological interventions for early-phase schizophrenia aims to develop a hierarchy of existing psychological treatments concerning their efficacy and tolerability, which will inform treatment guidelines.

2) STRUCTURE
The protocol has all the key elements: abstract, introduction, methodology, data analysis, and discussion.

a) Title
The title clearly describes the manuscript.

b) Abstract
The abstract is well composed, it is clearly wrote and it well reflects the content of the article.

c) Introduction
The introduction describes what authors hoped to achieve and it explains relevant previous researches on this topic.

d) Methodology
Authors explain materials and methods.In particular they well describe the study design, eligibility criteria, search strategy, outcomes, and statistical analysis.
e) Discussion /Conclusions Authors indicate how the present protocol / study could contain useful information, not only in a research perspective, but also in clinical practice.This is a topic of interest for growing literature and authors explain how this research can be informative for future studies.

g) Figures and tables
The supplementary figures well inform the reader and they are consistent for the aim of this paper.

3) LANGUAGE
The article is written in correct and fluent English.

4) RECOMMENDATION
The protocol / manuscript may have a significant interest and bring new perspectives for research in provide useful evidence-based information for the choice of individual treatment plans from a shared decision-making perspective.
Is the rationale for, and objectives of, the study clearly described?Yes

Is the study design appropriate for the research question? Yes
Are sufficient details of the methods provided to allow replication by others?Yes

Are the datasets clearly presented in a useable and accessible format? Yes
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: I'm involved in research projects on clinical, biological, pharmacological and rehabilitative aspects of mental disorders, in particular schizophrenia, mood disorders, autism and personality disorders.
I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Introduction:
-The word debilitating could be offending to certain patients.The authors are encouraged to use another term.
-Considering the main concept is early phase schizophrenia, the main prodromes of schizophrenia should be briefly discussed (e.g.vunerability group, attenuated psychosis group and BLIPS group which are the groups with the most evidence up to this day) as there is relevance regarding the therapeutic interventions for these groups.
-Please clarify the aim of this review as well as the main hypothesis.
Overall the introduction is well written with relevant literature.

Eligibility criteria:
-Main eligibility criteria should include specific criteria relevant to early phase schizophrenia considering the topic of this review.
-What are the exclusion criteria?

Secondary outcomes:
-Please provide psychometric properties and rationale for the scales used.
For the remaining portions of this protocol I have no further comment as it is clearly written and easy to follow.

Introduction:
The word debilitating could be offending to certain patients.The authors are encouraged to use another term.Answer: Thank you for this important feedback, we have now deleted the word and replaced it with the word "severe".Adapted (introduction): "Schizophrenia is a debilitating and severe and often life-long disorder, ranking among the 20 top causes of disability (1)." Considering the main concept is early phase schizophrenia, the main prodromes of schizophrenia should be briefly discussed (e.g.vunerability group, attenuated psychosis group and BLIPS group which are the groups with the most evidence up to this day) as there is relevance regarding the therapeutic interventions for these groups.
Answer: Thank you for your important comment.We also acknowledge that these essential groups can be associated with the development of schizophrenia.However, we intentionally choose not to include these groups in our review since our criterion is that a diagnosis already exists.It is possible that within the at-risk groups, ultimately, no illness or a different illness may develop.Already in the text (characteristics of participants): We will exclude studies in "at risk of psychosis" or "prodrome" populations, because such patients do not experience full-blown psychotic symptoms yet by definition.Added tot he introduction: "Schizophrenia can also manifest in the prelude to the full onset of symptoms through early warning signs such as social withdrawal, mistrust, sleep disturbances, and many more 6.However, these are not definitive indicators of the disorder but can be viewed as early warning signs."We also clarified in the section "characteristics of patients" now: "Participants must exhibit symptoms that match the criteria for schizophrenia or related disorders (schizophreniform, schizoaffective or delusional disorder, however diagnosed).Individuals with a specific vulnerability, brief limited intermittent psychotic symptoms or light psychotic symptoms will be excluded since the symptoms do not definitively suggest the development of schizophrenia." Please clarify the aim of this review as well as the main hypothesis.Answer: Thank you for the suggestion to address this more clearly.We have made some additions.Already in the text: "Knowledge of psychological interventions that are most efficacious in improving symptoms and preventing relapse in this critical population may allow to improve treatment planning and resource allocation in the health care sector." "Thus, it is currently unclear which are the most efficacious and acceptable psychological treatments for patients with schizophrenia at the early phase of the disorder.This underlines the need for a network meta-analysis producing a comprehensive synthesis of all the randomised evidence focusing on this particular population."

Added (objective): "Finding out which psychological intervention is most efficacious in treating patients
For the remaining portions of this protocol I have no further comment as it is clearly written and easy to follow.
Competing Interests: In the last three years SL has received honoraria for advising/consulting and/or for lectures and/or for educational material from Angelini, Boehringer Ingelheim, Eisai, Ekademia, GedeonRichter, Janssen, Karuna, Kynexis, Lundbeck, Medichem, Medscape, Mitsubishi, Neurotorium, Otsuka, NovoNordisk, Recordati, Rovi, Teva; JP from uniQure.The other authors declare that they have no competing interests.MH is a part-time employee of Get.On Institut für Gesundheitstrainings GmbH/HelloBetter.
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Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? Yes Are sufficient details of the methods provided to allow replication by others? Yes Are the datasets clearly presented in a useable and accessible format? Yes Competing Interests:
No competing interests were disclosed.

have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.
This is an open access peer review report distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? Yes Are sufficient details of the methods provided to allow replication by others? Yes Are the datasets clearly presented in a useable and accessible format?
Reviewer Expertise: Schizophrenia, Mental Health, Psychiatry, Virtual reality, Artificial Intelligence I confirm that I